SUMMARY Mitochondrial dysfunction and synaptic damage are early pathological features of Alzheimer?s disease (AD) and aging brains. Age is the strong risk factor for the development of AD, particularly late-onset AD. Mitochondria play a role in both AD and brain aging. Age-related metabolic changes induce accumulation of toxic reactive glucose-derived metabolite methylglyoxal (MG), highly reactive dicarbonyl specie, which serve as endogenous danger signals, causing direct cellular perturbation or through initiating the formation of MG- derived advanced glycation end products (AGEs), augmenting oxidative stress, and contributing importantly to neurodegeneration and cognitive impairment. Glyoxalase 1 (GLO1) is a key enzyme for clearance of MG/AGEs by detoxifying MG to prevent the formation of MG-derived AGEs. Impaired activity of GLO1 and increased levels of MG and MG-derived AGEs associated with cognitive dysfunction in aging and AD, suggesting that GLO1 may be important to prevent amyloid pathology of AD through its clearance of MG and A?. So far, the role of GLO1 on amyloid and mitochondrial pathology, synaptic degeneration, and cognitive dysfunction in AD remains unexplored. The link between GLOL1/MG and A? metabolism in AD and brain aging is unclear. We hypothesize that age- and AD-mediated the impairment of GLO1 function contributes to the accumulation of toxic metabolite MG and AGEs, leading to A? pathology, mitochondrial and synaptic degeneration, and cognitive decline, thus, scavenging MG by GLO1 may be of importance in preventing amyloid and mitochondrial pathology and attenuating synaptic injury. We will explore new insights into GLO1/MG/A? in age-related metabolic change and innate defense system linked to AD pathology and mitochondrial and synaptic injury.